This Alzheimer Caregiver Study has been exploring the physiological and psychological mechanisms that may be associated with increased health risk in groups of elderly spousal caregivers (CG). Results indicate that CG experience increased sympathoadrenalmedullary (SAM) arousal, which may be related to sleep disturbance, and associated with physiological changes previously linked to risk of cardiovascular (CV) disease, such as increase in circulating catecholamines, rise in the procoagulant factor D dimer, and the proinflammatory marker IL-6. Older CG show greatest changes. In the renewal we wish to develop a more complete mechanistic understanding of the stress to CV risk translation. The general hypotheses are that specific elements of the caregiving situation, such as problem behaviors of the care recipient and lack of respite induce affective arousal and sleep problems which favor a state of increased SAM arousal. Chronic SAM excitation favors the release of inflammatory markers such as IL-6, and a shift toward procoagulation. These physiological changes, if chronic, may lead to CV vulnerability, including hypertension and vascular endothelial injury. The buffering effects of coping that emphasize mastery will also be explored. A novel focus of this renewal application is our proposal to link the major markers of psychobiological stress related to caregiving (i.e., affective arousal, sleep disturbance, and biomarkers such as catecholamines, hemostatis variables, inflammatory markers) to indicators of CV injury including degree of endothelial injury, early signs of larger vessel pathology and baroreflex desensitization. The study design involves repeated observation of 120 spousal caregivers of Alzheimer patients and a comparison group of 60 non-caregivers. Using our unique strategy of "taking the laboratory to the home", participants will be assessed annually (with added assessments following placement or death of care recipient) with respect to their caregiving situation, psychological status, and several biological indicators (e.g. SAM arousal, sleep disturbance, pro-inflammatory and hemostasis molecules, baroreflex, measures of endothelial function, and large vessel disease). This study will provide a basis for a mechanistic understanding of the path from CG stress to CV morbidity in elderly CG, and opens the possibility of targeted interventions to reduce this risk.